title: Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons.
abstract: OBJECTIVE
  The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site.
  
  
  METHODS
  We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods.
  
  
  RESULTS
  We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice.
  
  
  CONCLUSIONS
  GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism.
authors.affiliation: Department of Neurophysiology, Medical Faculty, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: May
authors.forename: W
authors.initials: W
authors.lastname: Fleischer
authors.forename: O
authors.initials: O
authors.lastname: Kletke
authors.forename: H L
authors.initials: HL
authors.lastname: Haas
authors.forename: O A
authors.initials: OA
authors.lastname: Sergeeva
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D018757:GABA Modulators / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006632:Histamine / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007034:Hypothalamus, Posterior / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D006632:Histamine
keywords: GABA; histamine; microelectrode array; single-cell RT-PCR; whole-cell patch-clamp; zolpidem